1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention is related to the detection of drugs useful in the treatment of Alzheimer's disease. The invention is also related to compositions for treatment of Alzheimer's disease.
2. Related Art
Polymers of Abeta (Aβ), the 4.3 kD, 39–43 amino acid peptide product of the transmembrane protein, amyloid protein precursor (APP), are the main components extracted from the neuritic and vascular amyloid of Alzheimer's disease (AD) brains. Aβ deposits are usually most concentrated in regions of high neuronal cell death, and may be present in various morphologies, including amorphous deposits, neurophil plaque amyloid, and amyloid congophilic angiopathy (Masters, C. L., et al, EMBO J. 4:2757 (1985); Masters, C. L. et al., Proc. Natl. Acad. Sci. USA 82: 4245 (1985)). Growing evidence suggests that amyloid deposits are intimately associated with the neuronal demise that leads to dementia in the disorder.
The presence of an enrichment of the 42 residue species of Aβ in these deposits suggests that this species is more pathogenic. The 42 residue form of Aβ (Aβ1-42), while a minor component of biological fluids, is highly enriched in amyloid, and genetic studies strongly implicate this protein in the etiopathogenesis of AD. Amyloid deposits are decorated with inflammatory response proteins, but biochemical markers of severe oxidative stress such as peroxidation adducts, advanced glycation end-products, and protein cross-linking are seen in proximity to the lesions. To date, the cause of Aβ deposits is unknown, although it is believed that preventing these deposits may be a means of treating the disorder.
When polymers of Aβ are placed into culture with rat hippocampal neurons, they are neurotoxic (Kuo, Y-M., et al., J. Biol. Chem. 271:4077–81 (1996); Roher, A. E., et al., Journal of Biological Chemistry 271:20631–20635 (1996)). The mechanism underlying the formation of these neurotoxic polymeric Aβ species remains unresolved. The overexpression of Aβ alone cannot sufficiently explain amyloid formation, since the concentration of Aβ required for precipitation is not physiologically plausible. That alterations in the neurochemical environment are required for amyloid formation is indicated by its solubility in neural phosphate buffer at concentrations of up to 16 mg/ml (Tomski, S. & Murphy, R. M. Archives of Biochemistry and Biophysics 294:630 (1992)), biological fluids such as cerebrospinal fluid (CSF) (Shoji, M., et al., Science 258:126 (1992); Golde et al. Science, 255(5045):728–730 (1992); Seubert, P., et al., Nature 359:325 (1992); Haass, C., et al., Nature 359:322 (1992)) and in the plaque-free brains of Down's syndrome patients (Teller, J. K., et al., Nature Medicine 2:93–95 (1996)).
Studies into the neurochemical vulnerability of Aβ to form amyloid have suggested altered zinc and [H+] homeostasis as the most likely explanations for amyloid deposition. Aβ is rapidly precipitated under mildly acidic conditions in vitro (pH 3.5–6.5) (Barrow, C. J. & Zagorski, M. G., Science 253:179–182 (1991); Fraser, P. E., et. al., Biophys. J. 60:1190–1201 (1991); Barrow, C. J., et. al., J. Mol. Biol. 225:1075–1093 (1992); Burdick, D., J. Biol. Chem. 267:546–554 (1992); Zagorski, M. G. & Barrow, C. J., Biochemistry 31:5621–5631 (1992); Kirshenbaum, K. & Daggett, V., Biochemistry 34:7629–7639 (1995); Wood, S. J., et al., J. Mol. Biol. 256:870–877 (1996)). Recently, it has been shown that the presence of certain biometals, in particular redox inactive Zn2+ and, to a lesser extent, redox active Cu2+ and Fe3+, markedly increases the precipitation of soluble Aβ (Bush, A. I., et al., J. Biol. Chem. 268:16109 (1993); Bush, A. I., et al., J. Biol. Chem. 269:12152 (1994); Bush, A. I., et al., Science 265: 1464 (1994); Bush. A. I., et al., Science 268:1921 (1995)). At physiological pH, Aβ1-40 specifically and saturably binds Zn2+, manifesting high affinity binding (KD=107 nM) with a 1:1 (Zn2+:Aβ) stoichiometry, and low affinity binding (KD=5.2 μM) with a 2:1 stoichiometry.
The reduction by APP of copper (II) to copper (I) may lead to irreversible Aβ aggregation and crosslinking. This reaction may promote an environment that would enhance the production of hydroxyl radicals, which may contribute to oxidative stress in AD (Multhaup, G., et al., Science 271:1406–1409 (1996)). A precedence for abnormal Cu metabolism already exists in the neurodegenerative disorders of Wilson's disease, Menkes' syndrome and possibly familial amyotrophic lateral sclerosis (Tanzi, R. E. et al., Nature Genetics 5:344 (1993); Bull, P. C., et al., Nature Genetics 5:327 (1993); Vulpe, C., et al., Nature Genetics 3:7 (1993); Yamaguchi, Y., et al., Biochem. Biophys. Res. Commun. 197:271 (1993); Chelly, J., et al., Nature Genetics 3:14 (1993); Wang, D. & Munoz, D. G., J. Neuropathol. Exp. Neurol. 54:548 (1995); Beckman, J. S., et al., Nature 364:584 (1993); Hartmann, H. A. & Evenson, M. A., Med. Hypotheses 38:75 (1992)).
Although much fundamental pathology, genetic susceptibility and biology associated with AD is becoming clearer, a rational chemical and structural basis for developing effective drugs to prevent or cure the disease remains elusive. While the genetics of the disorder indicates that the metabolism of Aβ is intimately associated with the etiopatholgenesis of the disease, drugs for the treatment of AD have so far focused on “cognition enhancers” which do not address the underlying disease processes.